Towards Causal Mapping of Episodic Memory iEEG Networks Via Multi-method Brain Stimulation

The University of Chicago

Status: Invitation-only

Conditions: Hippocampal Activity; Memory Performance

Treatments: Other: TMS electrical stimulation parameters during cognitive and memory demands; Other: DES electrical stimulation parameters during cognitive and memory demands

Study type: Interventional

Funder types: Other

Identifiers

NCT07378332

IRB24-0486

Details and patient eligibility

About

Human intracranial electroencephalography (EEG) can provide brain-activity correlates of memory with high spatial and temporal resolution. This project will test functional relevance of these neural signals for memory behavioral performance using novel noninvasive and invasive stimulation methods. Findings will advance understanding of brain mechanisms for memory, as is needed to accelerate progress in the treatment of memory disorders.

Full description

Episodic memory impairment occurs when diseases impact the hippocampus and its network of interacting brain areas. Better understanding of brain mechanisms for memory is required to development treatments. This project will develop experimental approaches that use stimulation to manipulate brain-behavior relationships in humans and thereby directly test how the hippocampal network supports memory. Intracranial electroencephalography (iEEG) provides opportunities to study the neural basis of memory with high spatial and temporal resolution. Many experiments have identified iEEG signals associated with memory, for instance by comparing instances of memory success to failure. However, the functional relevance of these signals remains unclear, as such comparisons can identify signals of extraneous, co-occurring, cognitive processes. A routine approach to address this limitation in the behavioral neurosciences is via bi-directional manipulations, i.e., exogenous enhancement or inhibition of the putative neural process and tests of corresponding enhancement or inhibition of behavioral performance. This approach has been underutilized in human iEEG memory research, in part due to difficulties in reliably influencing memory or neural signals given currently available manipulations, such as direct electrical stimulation (DES) through iEEG electrodes. As a route to achieve bi-directional manipulation experiments in human iEEG memory research, this project utilizes a noninvasive electromagnetic stimulation tool that reliably and robustly influences hippocampal network activity and memory performance, called "hippocampal indirectly targeted stimulation" (HITS). HITS will be used with iEEG for the first time to identify activity patterns of the hippocampal network related to memory behavioral performance enhancement versus impairment. To rigorously test for behavioral relevance, we will use a closed-loop machine-learning approach to identify DES parameters that reproduce the hippocampal-network iEEG activity patterns generated by HITS, and then test whether delivery of DES to enhance or inhibit these hippocampal-network iEEG activity patterns produces corresponding enhancement versus impairment of memory behavioral performance. Thus, bidirectional manipulation will be used to directly/causally test iEEG signals of memory behavior. Group-level modeling of DES parameters that mimic the effects of HITS will be used to broaden the accessibility of bidirectional manipulations for future research that tests memory mechanisms in larger iEEG samples across multiple sites that lack the technical capability for HITS. Across three sites, will test whether bi-directional manipulations of hippocampal-network activity involvement in memory performance are more successful for HITS-informed DES versus DES based on a priori hypotheses. This exploratory project will thus build a foundation for future studies to rigorously test hippocampal-network support of memory behavioral performance using bi-directional experimental manipulations and will establish a collaboration of multidisciplinary researchers across multiple institutions to perform this innovative mechanistic memory research.

Enrollment: 44 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Age 18+ years old
• Native English speakers
• Normal or corrected-to-normal near and far vision

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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44 participants in 3 patient groups

TMS stimulation using HITS

Experimental group

Description:

Hippocampal indirectly targeted stimulation (HITS) will be applied in patients with epilepsy undergoing intracranial electroencephalography (iEEG) monitoring. iEEG signals of episodic memory behavioral performance will be obtained from clinical macroelectrodes and research microelectrodes in a specialized memory task involving encoding and retrieval of naturalistic scenes along with eye-movement tracking. Memory behaviors of interest will include recollection during old/new decisions and spatiotemporal replay of eye-movement patterns. HITS will be applied for \~2 s immediately before each scene onset during encoding, using parameters that have yielded enhanced versus impaired performance in this experiment design

Treatment:

Other: TMS electrical stimulation parameters during cognitive and memory demands

DES stimulation using HITS parameters

Experimental group

Description:

We will test the behavioral significance of iEEG correlates of memory enhancement and impairment using a rigorous approach involving DES. Direct electrical stimulation (DES) parameters will be identified that reproduce as closely as possible the iEEG signatures of memory enhancement or impairment caused by HITS. This will be accomplished using a closed-loop machine learning approach to maximize the similarity of the iEEG signals evoked by DES and the iEEG signals evoked by HITS, during memory encoding.

Treatment:

Other: DES electrical stimulation parameters during cognitive and memory demands

Normative model of DES

Experimental group

Description:

We will develop, test, and refine for future experiments a normative model of DES parameters to achieve experimental bi-directional manipulation of iEEG correlates of episodic memory. We will identify common features of the DES parameters that were algorithmically determined to mimic the iEEG signals of memory enhancement or impairment by HITS in the Experiment 2 dataset. Analyses will account for individual differences in stimulated electrode locations, in iEEG functional connectivity of stimulated electrodes, in the success of behavioral modification, and in the accuracy of mimicking the iEEG effects of HITS, to enable predictions about how to apply DES parameters in stimulation-naïve subjects given their idiosyncratic electrode placements and brain activity patterns.

Treatment:

Other: DES electrical stimulation parameters during cognitive and memory demands